|Title||Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Casuscelli, J, Weinhold, N, Gundem, G, Wang, L, Zabor, EC, Drill, E, Wang, PI, Nanjangud, GJ, Redzematovic, A, Nargund, AM, Manley, BJ, Arcila, ME, Donin, NM, Cheville, JC, R Thompson, H, Pantuck, AJ, Russo, P, Cheng, EH, Lee, W, Tickoo, SK, Ostrovnaya, I, Creighton, CJ, Papaemmanuil, E, Seshan, VE, A Hakimi, A, Hsieh, JJ|
|Date Published||2017 Jun 15|
Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%-10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.
|Alternate Journal||JCI Insight|